tbuckley/cabot-search huggingface dataset:
Abstract 11817: Induced Pluripotent Stem Cell-Derived Cardiac Disease Modeling for Studying Mitogenic Cardiomyopathy in Alström Syndrome
Authors: Robin Duelen, Domiziana Costamagna, Yoke Chin Chai, Ellen Caluwe, Hilde Gillijns, Johanna Jacobs, Ming Wu, Brigitte Malgrange, koenraad devriendt, Maurilio Sampaolesi, Stefan P Janssens
Journal: Circulation (2022)

Introduction: Cardiomyopathies are a prominent cause of heart failure and affect millions of people worldwide. We reported two case studies describing siblings with a mutation in the Alström 1 (ALMS1) gene causing Alström syndrome (ALMS), who developed mitogenic cardiomyopathy, characterized by delayed postnatal cardiomyocyte (CM) cell cycle arrest resulting in neonatal heart failure and death in early infancy. OBJECTIVES : To generate induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from ALMS patients and investigate molecular mechanisms of persistent CM proliferation in co-culture with ALMS1 fibroblasts. METHODS : We reprogrammed somatic cells from ALMS patients with mitogenic cardiomyopathy into iPSCs using Sendai virus technology and generated ALMS-specific iPSC-CMs using established in vitro differentiation protocols. We analyzed cell cycle progression by determining CM percentages in the G0/G1, S and G2/M phase using flow cytometry, and measured expression and secretion of periostin (POSTN) and collagens from ALMS1 fibroblasts in the extracellular matrix (ECM) using RT-QPCR and western blot. Finally, we investigated Hippo signaling by measuring expression and nuclear translocation of its downstream effectors YAP/TAZ using western blot and immunostaining. RESULTS : iPSC-CMs were successfully generated from ALMS patients and controls. ALMS1-deficient iPSC-CMs exhibited impaired ability to undergo cell cycle arrest, evidenced by a higher cell percentage in the G2/M phase. Furthermore, increased ECM levels of POSTN, a potent regulator of CM proliferation, were observed in co-cultures of ALMS1-deficient iPSC-CMs and ALMS1 fibroblasts. Finally, we found preliminary evidence of dysregulation of the Hippo pathway with altered cellular localization of YAP, and dysregulated total YAP and phosphorylated YAP. CONCLUSION : ALMS1-deficient iPSC-CMs recapitulate persistent postnatal proliferation observed in ALMS patients with mitogenic cardiomyopathy. Increased POSTN in the ECM and altered downstream Hippo signaling contribute to the mitogenic phenotype and suggest critical cues for future therapies aiming at stimulating CM turnover, a much-sought objective in cardiac repair to improve contractile function.
Abstract 11376: Catheter-Injectable Hydrogel for the Delivery of a Minicircle Encoding SDF-la as Therapy for Myocardial Infarction
Authors: Renato S Navarro, Narelli de Paiva Narciso, Aidan Gilchrist, Riley A Suhar, Sarah C Heilshorn
Journal: Circulation (2022)

Myocardial infarction ( MI ) is a leading cause of cardiovascular disease in the U.S. and abroad. Transient delivery of stromal cell-derived factor 1 ( SDF-1 α ) either through the delivery of protein-encoding genes or the protein itself has demonstrated improved cardiac function in preclinical models. However, the delivery of the therapy suffers from two limitations: (1) poor retention when injected into the contracting myocardium, and (2) rapid degradation of the protein, which requires prolonged activity to be therapeutically effective. To mitigate these limitations, we developed a catheter-injectable gel to deliver SDF-1 α encoding minicircles ( MC ). Design of gels for injection into the myocardium is historically challenging since traditional chemical strategies result in gels that are either too stiff and not catheter injectable or too weak and quickly ejected out of the contracting heart muscle. To address this challenge, our approach is to use dynamic covalent chemical (DCC) bonds, which are mechanically strong yet reversible, resulting in a shear-thinning gel (hence catheter injectable) and self-healing (hence retained in the contracting heart muscle). This biocompatible gel is chemically defined for future FDA approval and is synthesized from completely biodegradable polymers: recombinant elastin-like protein and hyaluronic acid. Rheological characterization identified several gel formulations that were easily extruded through a catheter (2 m long and .25 mm internal diameter) and rapidly reformed into a gel within 5 seconds after extrusion. To demonstrate the potential for clinical translatability, we evaluated the injectability and retention of the gel within the contracting rat myocardium. Our gel significantly improved the retention of a microparticle cargo by 200% compared to delivery in Matrigel. Current work is focused on evaluating the therapeutic efficacy of the gel in a rat myocardial infarct model when delivering a therapeutic cargo of SDF-1a-encoding MC. This biocompatible, catheter-injectable gel has great potential to significantly improve the delivery and retention of therapeutic cargo within mechanically active tissues, significantly improving the prolonged efficacy of MI therapies.
Abstract 11061: Incidence of Cancer in Hospitalized Adults With Congenital Heart Disease
Authors: Natalie E Caryl, Ciara June, Hunter Culbert, Riley Hellinger, Andrew Hoyer, Scott E Klewer, Michael D Seckeler
Journal: Circulation (2022)

Introduction: Many patients with congenital heart disease (CHD) are repeatedly exposed to low-dose ionizing radiation for diagnosis, treatment and long-term management of their care. Hypothesis: We hypothesized that these repeated exposures put CHD patients at higher risk for radiation-associated cancers (RAC). Methods: Review of Vizient (a national, administrative database) from 12/2018 - 12/2021 for admissions aged 18-85 years with ICD-10 codes for moderate or severe CHD and RAC (bladder, breast, colon, esophageal, leukemia/myeloma, liver, lung, ovarian and stomach). Demographics, hospital outcomes and costs were compared to admissions with RAC and no CHD (NO-CHD). Results: Out of 34,793 CHD admissions, 6.4% had RAC, and out of 24,999,735 NO-CHD admissions, 11.2% had RAC (p&lt;0.001; Table 1). CHD with RAC were younger, had longer length of stay, higher complications, in-hospital mortality and costs. Comparisons for each RAC type are in Table 2. There were higher rates of breast, liver and lung cancer in CHD (p&lt;0.05 for all) and higher costs for all CHD RAC except esophageal. Conclusions: This national database review shows increased incidence of some types of RAC (lung, liver and breast) in adults with CHD, with worse hospital outcomes and higher costs for several cancer types. While frequent radiation in the CHD population may contribute to these findings, it will be important to explore further. These findings also highlight the importance of adherence to the “as low as reasonably achievable” (ALARA) principle in the care of children and adults with CHD and stresses the importance of imaging modalities that do not use ionizing radiation.
Abstract 12221: Work Improvement With Novel Remote Monitoring System (Impella Connect) in Clinical Engineer Involving Acute Mechanical Circulatory Support
Authors: Hirota Hamatsu, Keitaro Domae, Daizo Kato, Naoya Hamada, TACHIBANA SHINYA, Takafumi Masai, Yoshiki Sawa
Journal: Circulation (2022)

Introduction: Recent innovations in mechanical circulatory support (MCS) enable physicians to deal with challenging cases with cardiogenic shock. As the number of MCS has increased, the excessive workload of clinical engineers (CEs) who manage MCS has become a serious problem. To overcome such situation, we introduced innovative remote monitoring system of circulatory assist pump catheters (Impella) called Impella Connect (IC) from 2020, which allows medical staff to monitor driving status and alarms of Impella in their mobile devices. Here we reported our experience of IC and the safety and efficacy of our protocol using IC for management of Impella. Methods: We identified 63 Impella cases for cardiogenic shock from 2018 to 2021 in our institution. We utilized Impella 2.5/CP in 53 cases and Impella 5.0 in 10 cases depending on their hemodynamic condition. Before introducing IC (nIC period: n=17), CEs were responsible for Impella management in all time periods and needed to work overtime to manage devices in night time. However, after introducing IC (IC periods: n=46), CEs were responsible only in daytime and non-MCS expert medical stuff were responsible in night time supporting by CEs’ remote monitoring with IC. We retrospectively evaluated the safety and efficacy of our management using IC. Results: Impella insertion was performed emergently in all cases and the 34 cases (53.9 %) were inserted in night time. Average support time was 6.5±0.6 days (nIC 7.7 vs. 6.0 days). We encountered 13 device trouble in nIC periods (purge system in 8, pressure sensor in 4 and pump malfunction in 1) and 14 in IC periods (purge system in 9, pressure sensor in 3 and pump malfunction in 2). Device trouble requiring intervention was not significantly different in both periods (nIC/IC 10 vs. 11 cases, p=0.85) and adverse event related to delayed or inappropriate response was not observed in both periods. The average of overtime working hours of CEs per month was significantly decreasing in IC periods (53.1±16.8 vs. 8.6±2.6 hours per month, p&lt;0.05). Conclusions: Our Impella management using novel remote monitoring system with Impella Connect was safe with no adverse events and effective to reduce overtime work of CEs, which resulted in work improvement of medical stuff involving MCS.
Abstract 12285: Low Risk of Stroke From Endocardial Ventricular Arrhythmia Ablation
Authors: Kanae Hasegawa, Zachary T Yoneda, Kenichi Tokutake, Travis D Richardson, Montgomery A Jay, Sharon T Shen, JC Estrada, Pablo J Saavedra, Amy Emerson, Marilyn L Walker, Gregory F Michaud, Arvindh N KANAGASUNDRAM, William G Stevenson
Journal: Circulation (2022)

Background: Recent studies increase concern for embolic events during radiofrequency ablation (RFA) for ventricular arrhythmias (VA). Objective: To assess peri-procedural symptomatic embolic events and anticoagulation regimens in patients undergoing endocardial RFA for VA. Methods: All patients undergoing endocardial RFA for VA from October 2018 to September 2021 were prospectively assessed for complications in hospital before discharge and at 30 days by clinic visit or phone call. Anticoagulation regimens were at the discretion of the treating physician. Results: There were 663 procedures in 616 patients (age 62 + 4 yrs, 73% structural heart disease, 48% sustained VT). Prior to the procedure 464 patients (70%) were taking an antithrombotic agent, either a direct acting anticoagulant agent (DOAC), warfarin, aspirin (ASA), other antiplatelet agent, or combinations (table 1); and the same type of agent was continued after ablation in 462. Of the 199 patients not receiving antithrombotic agents pre-ablation, 82.4% received 325 mg of ASA daily after the procedure, 3.0% received lower dose ASA, and 16 were started on DOAC or warfarin. There were 59 complications (8.9%) in 53 procedures. There were 2 strokes (0.3%); there were no transient ischemic attacks or other embolic events. There were 25 (3.8%) bleeding complications including 14 due to vascular access (2.1%) and 11 pericardial effusions (1.6%). Bleeding complications were more frequent in patients on the combination of antiplatelet and DOAC pre- or post-procedure. Conclusions: In this large single center series most patients undergoing VA ablation were receiving antithrombotic therapy pre-procedure that was continued post procedure. Full dose ASA was the most common post-procedure regimen for those not on pre-procedure anticoagulation. Stroke and emboli appear very rare. Combined antiplatelet and DOAC therapy is associated with increased bleeding risk.
Abstract 12721: Acute, High Dose Metformin at Reperfusion Decreases Infarct Size in the High-Risk Aging Heart
Authors: Zehui Li, Lauryn Bates, Hao Wang, Mohammad Fatmi, Qun Chen, Di Ren, Meredith Krause-Hauch, Ji Li, Edward J Lesnefsky
Journal: Circulation (2022)

Introduction: Elderly patients (age &gt; 75) sustain larger infarcts with greater mortality from STEMI despite successful TIMI III reperfusion. Elderly age is an independent risk despite correction for clinical and angiographic variables. Mitochondria (MITO) are key mediators of injury during ischemia (ISC) and reperfusion (R) in lab studies. The acute, transient blockade of the MITO electron transport chain (ETC) at complex I during R decreases infarct size in adult heart models. Metformin (MET) inhibits ETC complex I. Hypothesis: Acute, high dose MET given at R in high-risk aged STEMI model hearts will reduce infarct size. Methods: Young (3-6 mo) and aged (22-24 mo) C57BL/6J mice, male and female (NIA), underwent in vivo ISC-R surgery via 45 min LAD ligation. At 5 min pre-R, 2 mM MET (or vehicle) was injected via jugular vein. At 24-hr R infarction size and area at risk (AAR) were measured. Echo was performed pre-ISC and end-R. Results: MET treatment at R improved contractile function [ejection fraction (EF) and fractional shortening (FS)] following 24 hr R in both male and female aged groups as well as in the young heart (Figure A)(mean ± SD). MET at R substantially decreased infarct size in both sexes in the aged heart (Figure B) to a similar extent as in the young hearts. AAR was similar in all groups. Conclusions: Acute, high dose MET treatment directly before R decreased infarction and improved contractile function at 24 hr R in aged murine hearts. This is the initial step to move acute MET toward consideration as a cath lab treatment via intracoronary infusion immediately following R via PCI for elders suffering STEMI to reduce injury and preserve function.
Abstract 12733: Understanding the Care Priorities of Older Patients With Heart Failure
Authors: Susan D'Anna, Margaret Emmons, Deborah Cantlin, Carolyn DeMark, Mohammadtokir Mujtaba, Lauren Gilstrap
Journal: Circulation (2022)

Introduction: The average age of a Medicare beneficiary with heart failure (HF) is now 80 years old. As patients age, their care priorities may change. At present, “high quality” HF care is determined by the use of appropriate medications to forestall or reverse disease progression. The aim of this study to identify other care priorities among older adults with HF that should be considered when measuring the quality of HF care. Methods: We conducted semi-structured interviews with 41 patients ≥75 years old with HF. The oldest was 93 years old and the youngest was 75 with an average age of 82. Interviews were conducted in both the inpatient (n=23) and outpatient/clinic (n=18) settings. Patients were asked a series of 10 questions focused on care priorities and the characteristics of “high quality” care. Interviews were recorded and transcribed. The longest interview was 19:59 minutes, the shortest was 4:20 minutes and the average was 10:32 minutes. Recordings were listened to while reviewing the transcripts, then analyzed and coded for thematic analysis. Results: The domains of high quality care highlighted by older patients are described in Figure 1. The most important aspects of HF care included: “getting the right medicine” and “making me comfortable as long as I can be.” Patients defined high quality care as: “a team that listens” and “follows up.” A high quality provider was distinguished from a low quality provider by “honesty,” “compassion” and “the ability to listen.” When asked how providers/teams should be evaluated, patients recommended metrics that captured: “knowledge,” “communication” and “really caring.” Discussion: Current HF quality metrics capture less than half of the care domains that are important to older patients with HF. Additional work is needed to create novel quality metrics to incentivize all domains of high quality HF care.
Abstract 11876: The Selenoprotein, Vimp, Selectively Regulates a Newly Defined Non-Canonical Form of Proteasomal Degradation at the ER to Modulate Cardiac Hypertrophy
Authors: Erik Blackwood, Lauren MacDonnell, Donna Thuerauf, Alina S Bilal, Christopher C Glembotski
Journal: Circulation (2022)

Introduction: Canonical endoplasmic reticulum (ER) associated degradation (ERAD) adaptively degrades misfolded potentially toxic ER proteins that can accumulate in cells under a variety of stresses. However, roles for ERAD in vivo in potentially pathological conditions have not been well studied. Hypothesis: Here, we examined a functional component of ERAD, VCP-interacting membrane protein (VIMP), positing that decreasing VIMP would decrease canonical ERAD, which would be maladaptive in a mouse model of pathological cardiac hypertrophy. Methods: Mice were injected with AAV9 to transduce cardiomyocytes with either a shRNA targeting VIMP (shVIMP), or ectopic wild-type or an ERAD-deficient AAV-FLAGVIMP and subjected to pressure overload-induced cardiac hypertrophy. Mice were also injected with a novel AAV expressing a canonical ERAD substrate to monitor the rate of ERAD in vivo for the first time in any organ system. Results: Unexpectedly, both VIMP knockdown and overexpression in mouse hearts decreased canonical ERAD while only VIMP knockdown adaptively decreased pathological cardiac hypertrophy. We evaluated the effects of VIMP gain and loss of function on ERAD-mediated degradation of a cytosolic pro-growth kinase, serum/glucocorticoid-regulated kinase 1, SGK1, which we showed here to contribute to pathological cardiac hypertrophy and to be a non-canonical, i.e non-ER localized substrate for ERAD. In contrast to its effect on canonical ERAD, VIMP overexpression decreased noncanonical ERAD-mediated degradation of SGK1, which accounted for the maladaptive effects of increased VIMP in the heart. We found that DERLIN1 was responsible for increasing ERAD-mediated SGK1 degradation, which accounted for the suppression of pathological cardiac hypertrophy when VIMP was knocked down. Conclusions: Thus, the relative levels of VIMP and DERLIN1 comprise a molecular switch mechanism that regulates a newly defined non-canonical ERAD-mediated degradation of SGK1, a critical signaling kinase contributing to pathological cardiac hypertrophy. Furthermore, this noncanonical ERAD is of unique importance in cardiomyocytes as these effects of VIMP gain and loss of function were not observed in cardiac fibroblasts from the same mouse hearts.
Abstract 11886: Unique Insights of Pressure-Volume Loop Analysis During LVAD Ramp Study
Authors: Paul J Scheel, Ilton M Cubero Salazar, Matthew Kauffman, Alexandra Weller, Fatimah Alkhunaizi, Monica Mukherjee, Nisha A Gilotra, Kavita Sharma, Ahmet Kilic, Ryan J Tedford, Steven Hsu
Journal: Circulation (2022)

Introduction: Late right ventricular (RV) failure in left ventricular assist device (LVAD) patients leads to poor outcomes and mortality. Traditional hemodynamic assessment of RV function may lack sensitivity. Invasive pressure-volume loop assessment of RV function may prove more enlightening than currently available measures. Methods: Pressure-volume loop-derived RV end-systolic elastance (Ees) and effective arterial elastance (Ea)—indices of load-independent RV contractility and summated pulmonary arterial (PA) afterload respectively—were determined for control (n=14), PH (n=38), and LVAD (n=12) patients referred for right heart catheterization. LVAD patients were further dichotomized by referral reason: routine assessment vs. clinical heart failure (HF) (n=6 each). Results: At baseline, LVAD patients had lower RV Ees versus both PH (0.21 vs 0.41 mmHg/mL, p&lt;0.001) and control (0.21 vs. 0.36 mmHg/mL, p=0.05) patients. Adjusting for age and afterload, RV-PA coupling, indexed by the ratio of Ees/Ea, was significant lower in LVAD vs matched non-LVAD patients (0.37 vs 0.65, p=0.01). Among LVAD patients, RV-PA coupling was significantly worse in those with clinical HF (0.26 vs 0.49, p=0.002), corresponding with depressed cardiac index (1.6 vs 2.3 L/min/m 2 , p=0.04) and a trend towards higher biventricular filling pressures. RV-PA coupling also responded differently with respect to speed change: while Ees/Ea improved with speed increase in well-compensated LVAD patients, it declined in those with HF (p=0.02 for interaction term, see Figure), driven by declining Ees. Conclusion: Intrinsic RV contractility is worse in LVAD patients versus control and non-LVAD PH; this drives significantly worse RV-PA coupling in LVAD patients. In LVAD patients with HF, RV-PA coupling is significantly reduced and not necessarily improved by increases in speed.
Abstract 11052: Implanting Cardiovascular Electronic Devices With a Biologic Tissue Envelope Improves Healing and Facilitates Reoperative Procedures
Authors: John N Catanzaro, Kenneth C Bilchick, Thomas J Christopher, Benjamin A DSouza, ZIAD F ISSA, Afolabi O Sangosanya, Aaditya Vora, Hirad Yarmohammadi, Thomas F Deering, Jerome B Riebman
Journal: Circulation (2022)

Introduction: Fibrous encapsulation of implanted cardiovascular implantable electronic devices (CIED) may create a hostile environment during device reoperation. An acellular biologic extracellular tissue CIED envelope (CanGaroo®, Aziyo Biologics) may attenuate host foreign body response to the implant, decrease fibrosis and enable adaptive vascularized healing to facilitate reoperation &amp; decrease complications. Hypothesis: CIED implant site findings at reoperation differ in patients who previously received a biologic envelope (BIO) vs no envelope (NO-BIO) at time of device implant. Methods: Patients undergoing reoperative CIED procedures (9 BIO, 12 NO-BIO) were assessed (medical profiles, procedural notes, scaled scoring of intra-operative assessments &amp; tissue biopsy histology of the implant pocket). Results: There were no significant cohort differences in mean age, gender or implant location. Median capsular lead adhesion classification (semi-qualitative scale) was significantly lower (less severe) for BIO implants (p=0.02) [Fig. 1, double arrows]. Physicians scored BIO reoperations (10-pt scale) as 39% less difficult in generator mobilization (p=0.04), 43% less difficult in lead mobilization (p=0.04) and 45% less overall procedural difficulty (p=0.01). BIO pockets required 63% fewer capsulectomies (p=0.18). Multipoint histologic assessment of fibrotic capsule thickness (16 matrixed measurements, 5 BIO vs 11 NO-BIO with complete datasets) revealed a 39% reduction in BIO implant pockets (p=0.05), with no significant differences between groups in capsule mature collagen density [Fig. 1, single arrows]. Conclusions: When a BIO envelope was used at initial CIED implantation (vs no envelope), we observed significantly less fibrous lead entrapment, easier generator &amp; lead mobilization, and thinner mature fibrotic capsules at reoperation. Biologic tissue envelopes may prevent operative complications and enhance clinical outcomes.